TRPC1 links calcium signaling to cellular senescence in the protection against posttraumatic osteoarthritis

Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we have demonstrated that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence–associated cartilage breakdown during mechanical and inflammatory challenge. We revealed that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a nonredundant role in calcium signaling in chondrocytes. Trpc1^–/– mice subjected to destabilization of the medial meniscus–induced OA developed a more severe OA phenotype than WT controls. During early OA development, Trpc1^–/– mice displayed an increased chondrocyte survival rate; however, remaining cells displayed features of senescence including p16^INK4a expression and decreased Sox9. RNA-Seq identified differentially expressed genes related to cell number, apoptosis, and extracellular matrix organization. Trpc1^–/– chondrocytes exhibited accelerated dedifferentiation, while demonstrating an increased susceptibility to cellular senescence. Targeting the mechanism of TRPC1 activation may be a promising therapeutic strategy in OA prevention.